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1.  Self-Predictions of Prospective Memory in HIV-Associated Neurocognitive Disorders: Evidence of a Metamemory Deficit 
HIV-associated neurocognitive disorders (HAND) are associated with deficits in prospective memory (PM; “remembering to remember”), conferring risk of daily functioning declines. However, self-perceptions of PM functioning are not reliably associated with PM performance in HIV, suggesting a possible deficit in awareness of PM abilities (meta-PM). Our study examined meta-PM in HAND and its correlates using self-predictions of laboratory-based PM performance. Performance-based PM abilities, self-reported prediction of PM performance, and PM complaints in everyday life were assessed in 49 individuals with HAND, 93 HIV+ without HAND (HIV+ noHAND), and 121 seronegative adults (HIV−). After controlling for group-level differences, HAND was associated with a greater number of PM symptoms in everyday life and worse PM performance when compared with both HIV+ noHAND and HIV− samples. Although HAND individuals reported somewhat lower predictions regarding their laboratory PM performance relative to the other study groups, they nevertheless exhibited significantly greater inaccurate overconfidence in time-based PM abilities. Within the HAND group, overconfidence in time-based meta-PM was associated with executive dysfunction and antiretroviral (ARV) nonadherence. HAND individuals evidenced a moderate deficit in awareness of PM functioning characterized by overconfidence in time-based PM abilities. Overconfidence in PM may result in absence of compensatory strategy use, and lead to increased errors in daily functioning (e.g., ARV nonadherence).
doi:10.1093/arclin/acu061
PMCID: PMC4296161  PMID: 25404005
Executive functions; Metacognition; Everyday functioning
2.  Are Time- and Event-based Prospective Memory Comparably Affected in HIV Infection?† 
According to the multi-process theory of prospective memory (ProM), time-based tasks rely more heavily on strategic processes dependent on prefrontal systems than do event-based tasks. Given the prominent frontostriatal pathophysiology of HIV infection, one would expect HIV-infected individuals to demonstrate greater deficits in time-based versus event-based ProM. However, the two prior studies examining this question have produced variable results. We evaluated this hypothesis in 143 individuals with HIV infection and 43 demographically similar seronegative adults (HIV−) who completed the research version of the Memory for Intentions Screening Test, which yields parallel subscales of time- and event-based ProM. Results showed main effects of HIV serostatus and cue type, but no interaction between serostatus and cue. Planned pair-wise comparisons showed a significant effect of HIV on time-based ProM and a trend-level effect on event-based ProM that was driven primarily by the subset of participants with HIV-associated neurocognitive disorders. Nevertheless, time-based ProM was more strongly correlated with measures of executive functions, attention/working memory, and verbal fluency in HIV-infected persons. Although HIV-associated deficits in time- and event-based ProM appear to be of comparable severity, the cognitive architecture of time-based ProM may be more strongly influenced by strategic monitoring and retrieval processes.
doi:10.1093/arclin/acr020
PMCID: PMC3081684  PMID: 21459901
AIDS dementia complex; Episodic memory; Executive functions; Neuropsychological assessment
3.  Neurocognitive Change in the Era of HIV Combination Antiretroviral Therapy: The Longitudinal CHARTER Study 
CNS HIVAnti-Retroviral Therapy Effects Research examined incidence and predictors of neurocognitive (NC) change in 436 human immunodeficiency virus (HIV)-infected adults over 4–7 semiannual visits; 22.7% evidenced NC decline and 16.5% NC improvement. These changes were predicted by HIV disease and treatment factors, demographics, and comorbid conditions.
Background. Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) can show variable clinical trajectories. Previous longitudinal studies of HAND typically have been brief, did not use adequate normative standards, or were conducted in the context of a clinical trial, thereby limiting our understanding of incident neurocognitive (NC) decline and recovery.
Methods. We investigated the incidence and predictors of NC change over 16–72 (mean, 35) months in 436 HIV-infected participants in the CNS HIV Anti-Retroviral Therapy Effects Research cohort. Comprehensive laboratory, neuromedical, and NC assessments were obtained every 6 months. Published, regression-based norms for NC change were used to generate overall change status (decline vs stable vs improved) at each study visit. Survival analysis was used to examine the predictors of time to NC change.
Results. Ninety-nine participants (22.7%) declined, 265 (60.8%) remained stable, and 72 (16.5%) improved. In multivariable analyses, predictors of NC improvements or declines included time-dependent treatment status and indicators of disease severity (current hematocrit, albumin, total protein, aspartate aminotransferase), and baseline demographics and estimated premorbid intelligence quotient, non-HIV-related comorbidities, current depressive symptoms, and lifetime psychiatric diagnoses (overall model P < .0001).
Conclusions. NC change is common in HIV infection and appears to be driven by a complex set of risk factors involving HIV disease, its treatment, and comorbid conditions.
doi:10.1093/cid/ciu862
PMCID: PMC4303775  PMID: 25362201
cognitive change; HIV; antiretroviral therapy; comorbidities
4.  Typologies of positive psychotic symptoms in methamphetamine dependence 
Background and Objectives
Understanding methamphetamine associated psychotic (MAP) symptom typologies could aid in identifying individuals at risk of progressing to schizophrenia and guide early intervention.
Methods
Latent class analysis (LCA) of psychotic symptoms collected from 40 methamphetamine dependent individuals with a history of psychotic symptoms but no history of a primary psychotic disorder.
Results
Three typologies were identified. In one, persecutory delusions dominated (Type 1), in another persecutory delusions were accompanied by hallucinations (Type 2), and in the third a high frequency of all the assessed hallucinatory and delusional symptoms was observed (Type 3).
Discussion and Conclusion
MAP is a heterogeneous syndrome with positive symptom typologies.
Scientific Significance
This study represents the first attempt at identifying typologies of MAP and highlights the potential utility of LCA in future large-scale studies.
doi:10.1111/ajad.12160
PMCID: PMC4369467  PMID: 25864598
psychosis; stimulant; profile; structure; latent class
5.  Refining a Personalized mHealth Intervention to Promote Medication Adherence among HIV+ Methamphetamine Users 
AIDS care  2014;26(12):1477-1481.
Mobile health (mHealth) interventions to promote antiretroviral therapy (ART) adherence have shown promise; however, among persons living with HIV who abuse methamphetamine (MA) effective tailoring of content to match the expressed needs of this patient population may be necessary. This study aimed: 1) to understand patient perspectives of barriers and facilitators of ART adherence among people with HIV who use MA, and 2) to obtain feedback on the thematic content of an mHealth intervention in order to tailor the intervention to this subgroup. Two separate focus groups, each with ten HIV+/MA+ individuals, were conducted. Transcribed audio recordings were qualitatively analyzed to identify emergent themes. Interrater reliability of themes was high (mean Kappa=.97). Adherence barriers included MA use, misguided beliefs about ART adherence, memory and planning difficulties, social barriers and perceived stigma, and mental heath issues. Facilitators of effective ART adherence were cognitive compensatory strategies, promotion of well being, health care supports, adherence education, and social support. Additionally, the focus groups generated content for reminder text messages to be used in the medication adherence intervention. This qualitative study demonstrates feasibility of using focus groups to derive patient-centered intervention content to address the health challenge at hand in targeted populations. Clinical Trial # NCT01317277
doi:10.1080/09540121.2014.924213
PMCID: PMC4188758  PMID: 24911433
Focus groups; methamphetamine; antiretroviral treatment; adherence; mHealth; short message service
6.  Impact of COMT Val158Met on executive functioning in the context of HIV and methamphetamine 
The catechol-O-methyltransferease (COMT) Val allele has been linked to executive dysfunction among healthy individuals. The nature of this relationship is unknown in the context of HIV infection and/or methamphetamine (METH) dependence, two conditions that can alter dopaminergic system functioning. We sought to determine if the putative relationship between COMT and executive dysfunction could be observed among individuals with and without HIV-infection and/or METH dependence, and to explore the specificity of this relationship by examining other cognitive domains. Utilizing an existing cohort of 229 men with and without HIV infection and/or METH dependence we found that Met/Met carriers within the HIV-only and control groups, displayed better executive functioning compared to Val/Val and Val/Met carriers. However, this effect was attenuated in the METH-only and comorbid (ie, HIV+/METH+) groups. Examination of other neurocognitive domains were not consistent with effects found for executive functioning. Results support the presumed neuroprotective effect of Met/Met genotype on executive functioning among HIV-only and control groups. Among METH-only and comorbid groups, the slower rate of dopamine clearance conferred by the Met/Met genotype may increase the risk of adverse effects of METH, resulting in comparable executive dysfunction to that of Val allele carriers.
doi:10.2147/NBHIV.S8245
PMCID: PMC3782745  PMID: 24078782
Val158Met; Endophenotype; Executive Function
7.  Attention-Deficit/Hyperactivity Disorder Among Chronic Methamphetamine Users: Frequency, Persistence, and Adverse Effects on Everyday Functioning 
Addictive behaviors  2013;38(12):2874-2878.
Aims
Attention-Deficit/Hyperactivity Disorder (ADHD) is widely regarded as a common comorbidity of methamphetamine (MA) dependence, but the frequency, persistence, and real-world impact of ADHD among MA users is not known.
Methods
Four hundred individuals with MA use disorders within 18 months of evaluation and 355 non-MA using comparison subjects completed a comprehensive neuropsychiatric research battery, including self-report measures of everyday functioning.
Results
In logistic regression models adjusting for potential confounds, lifetime diagnoses of ADHD as determined by a structured clinical interview were significantly more prevalent among the MA participants (21%) versus comparison subjects (6%), particularly the hyperactive and combined subtypes. MA use was also associated with an increased persistence of combined subtype of ADHD into adulthood. Among the MA users, lifetime ADHD diagnoses were uniquely associated with greater concurrent risk of declines in instrumental activities of daily living, elevated cognitive symptoms in day-to-day life, and unemployment.
Conclusions
Findings indicate that ADHD is prevalent among chronic MA users, who are at increased risk for persistence of childhood diagnoses of ADHD into their adult years. ADHD also appears to play an important role in MA-associated disability, indicating that targeted ADHD screening and treatment may help to improve real-world outcomes for individuals with MA use disorders.
doi:10.1016/j.addbeh.2013.08.010
PMCID: PMC3805791  PMID: 24018233
Substance Abuse; Developmental Disorder; Comorbidity; Functioning; Disability; Neuropsychiatry
8.  Preliminary evidence of ethnic divergence in associations of putative genetic variants for methamphetamine dependence 
Psychiatry research  2010;178(2):295-298.
Research into the biological processes that increase susceptibility to methamphetamine dependence has been conducted primarily in Asian populations. Using a case-control design this study’s purpose was to explore, among a population of methamphetamine-dependent Caucasians, six putative single nucleotide polymorphisms previously found to be associated with methamphetamine dependence in Asian populations. 193 non-psychotic males (117 methamphetamine-dependent and 76 controls) were genotyped for variants located in six genes (AKT1, ARRB2, BDNF, COMT, GSTP1, OPRM1). Genotypic and allelic frequencies, odds ratios, and 95% confidence intervals were calculated. None of the putative gene associations were significantly replicated in our sample of Caucasian men. Effect size comparisons suggest a trend toward allelic divergence for arrestin beta 2 (ARRB2) and glutathione S-transferase P1 (GSTP1) and allelic convergence for brain-derived neurotrophic factor (BDNF). Results provide preliminary support for further exploration and validation of candidate SNPs for METH dependence reported among Asian populations across other ethnic/ancestral groups.
doi:10.1016/j.psychres.2009.07.019
PMCID: PMC2902702  PMID: 20478633
AKT1; COMT; OPRM1; ARRB2; BDNF; GSTP1
9.  Methamphetamine Use Parameters Do Not Predict Neuropsychological Impairment in Currently Abstinent Dependent Adults 
Drug and alcohol dependence  2009;106(2-3):154.
Methamphetamine (meth) abuse is increasingly of public health concern and has been associated with neurocognitive dysfunction. Some previous studies have been hampered by background differences between meth users and comparison subjects, as well as unknown HIV and hepatitis C (HCV) status, which can also affect brain functioning. We compared the neurocognitive functioning of 54 meth dependent (METH+) study participants who had been abstinent for an average of 129 days, to that of 46 demographically comparable control subjects (METH-) with similar level of education and reading ability. All participants were free of HIV and HCV infection. The METH+ group exhibited higher rates of neuropsychological impairment in most areas tested. Among meth users, neuropsychologically normal (n=32) and impaired (n=22) subjects did not differ with respect to self-reported age at first use, total years of use, route of consumption, or length of abstinence. Those with motor impairment had significantly greater meth use in the past year, but impairment in cognitive domains was unrelated to meth exposure. The apparent lack of correspondence between substance use parameters and cognitive impairment suggests the need for further study of individual differences in vulnerability to the neurotoxic effects of methamphetamine.
doi:10.1016/j.drugalcdep.2009.08.010
PMCID: PMC2814900  PMID: 19815352
Methamphetamine; Stimulant; Motor impairment; Neuropsychological; Cognitive impairment; Drug exposure; Predictors
10.  Neurobehavioral effects of HIV infection among former plasma donors in rural China 
Journal of neurovirology  2008;14(6):536-549.
The HIV epidemic in China has expanded rapidly in recent years, but little is known about the prevalence and features of HIV Associated Neurocognitive Disorders (HANDs) in this part of the world. We administered a comprehensive Western neuropsychological (NP) test battery to 203 HIV+ and 198 HIV-former plasma donors in the rural area of Anhui province. We found that 26% in the HIV- sample, and 46% in the HIV+ sample were infected with HCV, which can also have CNS effects. To classify NP impairment, we developed demographically corrected test norms based upon individuals free of both infections (N=141). Using a global summary score, NP impairment was found in 34.2% of the HIV mono-infected group and 39.7% of the co-infected group, as compared to 12.7% of the uninfected controls (p<.001). HIV+ participants with AIDS were more likely to be impaired (43%) than non-AIDS individuals (29%, p<.05). Lastly, when all infection groups were combined, participants with NP impairment reported more cognitive complaints (p<.01) and increased dependence in everyday functioning (p=.01). In sum, NP impairment in this large rural Chinese sample was associated with both HIV and HCV infections, and the impairment's prevalence, severity, and pattern were similar to those reported by Western studies. Clinical significance of NP impairment in this population is suggested by the participants’ reports of reduced everyday functioning. These findings indicate that HAND is likely to be an important feature of HIV infection in developing countries, underscoring the need for international efforts to develop CNS relevant treatments.
doi:10.1080/13550280802378880
PMCID: PMC2889205  PMID: 18991068
HIV; HCV; neurocognitive disorders; China
11.  Risk for cognitive impairment among HIV-infected persons with bipolar disorder  
Clinicians and clinical neuroscientists are aware that individuals with bipolar disorder are at greater risk for developing serious medical, psychiatric, and substance-use comorbidities as compared with the general population.1,2 Less widely appreciated, however, is the observation that HIV infection appears to be more prevalent among persons with bipolar disorder and that both conditions pose significant risk for cognitive impairment.3 Higher rates of HIV infection among persons with bipolar disorder should not be surprising, given that infection and transmission of HIV involves risk factors that converge with bipolar disorder (eg, impulsivity, substance abuse). These factors likely also worsen adherence to treatment for both bipolar and HIV illness, and may adversely impact health-related quality of life and therapeutic outcomes. The public health consequence may be that nonadherence to antiretroviral therapy could lead to higher rates of transmission of treatment-resistant strains of HIV that can evolve with sporadic adherence. The intersection of bipolar disorder and HIV therefore merits discussion by clinicians, researchers, and policy makers.
PMCID: PMC3181874
12.  Methamphetamine use and neuropsychiatric factors are associated with antiretroviral nonadherence 
AIDS care  2012;24(12):1504-1513.
The present study assesses the impact of methamphetamine (METH) on antiretroviral (ART) adherence among HIV+ persons, as well as examines the contribution of neurocognitive impairment and other neuropsychiatric factors (i.e., major depressive disorder (MDD), Antisocial Personality Disorder (ASPD), and Attention Deficit Disorder (ADHD)) for ART nonadherence. We examined HIV+ persons with DSM-IV-diagnosed lifetime history of METH abuse/dependence (HIV+/METH+; n = 67) as compared to HIV+ participants with no history of METH abuse/dependence (HIV+/METH−; n = 50). Ancillary analyses compared these groups with a small group of HIV+/METH+ persons with current METH abuse/dependence (HIV+/CU METH+; n = 8). Nonadherence was defined as self-report of any skipped ART dose in the last four days. Neurocognitive functioning was assessed with a comprehensive battery, covering seven neuropsychological domains. Lifetime METH diagnosis was associated with higher rates of detectable levels of plasma and CSF HIV RNA. When combing groups (i.e., METH+ and METH− participants), univariate analyses indicated co-occurring ADHD, ASPD, and MDD predicted ART nonadherence (p’s<0.10; not lifetime METH status or neurocognitive impairment). A significant multivariable model including these variables indicated that only MDD uniquely predicted ART nonadherence after controlling for the other variables (p<0.05). Ancillary analyses indicated that current METH users (use within 30 days) were significantly less adherent (50% prevalence of nonadherence) than lifetime METH+ users and HIV+/METH-participants, and that neurocognitive impairment was associated with nonadherence (p’s<0.05). METH use disorders are associated with worse HIV disease outcomes and ART medication nonadherence. Interventions often target substance use behaviors alone to enhance antiretroviral treatment outcomes; however, in addition to targeting substance use behaviors, interventions to improve ART adherence may also need to address coexisting neuropsychiatric factors and cognitive impairment to improve ART medication taking.
doi:10.1080/09540121.2012.672718
PMCID: PMC3466384  PMID: 22530794
HIV/AIDS; Cognition; Medication Adherence; Antiretroviral; Methamphetamine
13.  Absence of neurocognitive impairment in a large Chinese sample of HCV-infected injection drug users receiving methadone treatment 
Drug and alcohol dependence  2014;137:29-35.
Background
Prior research has demonstrated neuropsychological (NP) impairment in persons with histories of injection drug use (IDU), hepatitis C virus (HCV) infection, and methadone maintenance treatment (MMT), individually, but little is known about the NP effects of these three risk factors in combination. This issue is particularly important in China, which is addressing its highly HCV-comorbid IDU epidemic with widespread government sponsored MMT, especially in light of recent evidence suggesting that methadone may be neuroprotective in some circumstances.
Methods
We administered a comprehensive NP test battery to 195 Chinese heroin IDU individuals taking MMT (IDU+ group), the majority of whom were also HCV+ (87%; n = 169), and compared their NP performance to that of 198 demographically comparable, non-IDU Chinese controls (IDU− group). All participants in both groups tested negative for HIV infection, which is also a common comorbidity in the Chinese IDU population.
Results
The IDU+ group did not have an increased rate of global NP impairment, or perform significantly worse on any individual NP test measure. Within the IDU+ group, liver disease characteristics and reported details of heroin use were not significantly associated with NP performance.
Conclusion
Failure to detect NP impairment in IDU+ subjects with or without HCV infection was surprising, particularly considering the previously demonstrated sensitivity of our NP battery to neurocognitive disorders associated with HIV infection in China. One possible explanation, which should be explored in future research, is the potential neuroprotective effect of methadone in the context of HCV infection and/or heroin withdrawal.
doi:10.1016/j.drugalcdep.2013.12.021
PMCID: PMC3961522  PMID: 24508003
HCV; Neurocognitive impairment; China; Injection drugs
15.  Individualized Texting for Adherence Building (iTAB): Improving Antiretroviral Dose Timing Among HIV-Infected Persons with Co-occurring Bipolar Disorder 
AIDS and behavior  2015;19(3):459-471.
HIV+ persons with co-occurring bipolar disorder (HIV+/BD+) have elevated rates of medication nonadherence. We conducted a 30-day randomized controlled trial of a two-way, text messaging system, iTAB (n = 25), compared to an active comparison (CTRL) (n = 25) to improve antiretroviral (ARV) and psychotropic (PSY) adherence and dose timing. Both groups received medication adherence psychoeducation and daily texts assessing mood. The iTAB group additionally received personalized medication reminder texts. Participants responded to over 90 % of the mood and adherence text messages. Mean adherence, as assessed via electronic monitoring caps, was high and comparable between groups for both ARV (iTAB 86.2 % vs. CTRL 84.8 %; p = 0.95, Cliff’s d = 0.01) and PSY (iTAB 78.9 % vs. CTRL 77.3 %; p = 0.43, Cliff’s d = −0.13) medications. However, iTAB participants took ARVs significantly closer to their intended dosing time than CTRL participants (iTAB: 27.8 vs. CTRL: 77.0 min from target time; p = 0.02, Cliff’s d = 0.37). There was no group difference on PSY dose timing. Text messaging interventions may represent a low-burden approach to improving timeliness of medication-taking behaviors among difficult-to-treat populations. The benefits of improved dose timing for long-term medication adherence require additional investigation.
doi:10.1007/s10461-014-0971-0
PMCID: PMC4359057  PMID: 25504449
Medication adherence; HIV/AIDS; Bipolar disorder; mHealth; Behavior modification; Randomized controlled trial; Intervention research
16.  The concomitant use of second generation antipsychotics and long term antiretroviral therapy may be associated with increased cardiovascular risk 
Psychiatry research  2014;218(0):201-208.
To study the effect of concurrent use of second-generation antipsychotics (SGAs) on metabolic syndrome components conferring increased cardiovascular risk in a sample of HIV-infected adults taking ART. A retrospective study of participants consecutively recruited at the UCSD HIV Neurobehavioral Research Program examined effects of combined ART and SGAs on body mass index (BMI), nonfasting serum lipids, diabetes mellitus (DM) incidence, and mean arterial pressure (MAP). Metabolic outcome variables and covariates were compared using t-tests, Chi-squared or Fisher’s exact tests. Linear and logistic multivariable models explored metabolic outcomes for participants taking (SGA+) or not taking (SGA−) concomitant SGAs, after controlling for demographic and HIV disease- and ART-related covariates. Of 2229 HIV-infected participants, 12% (N=258) were treated with SGAs. In multivariable models adjusted for relevant covariates, the SGA+ group had significantly higher mean triglycerides, significantly higher odds of DM, significantly higher mean arterial pressures and marginally higher BMI. Use of SGAs in HIV-infected adults taking ART was independently associated with worse indicators of metabolic syndrome and cardiovascular risk. Aggressive monitoring for the metabolic complications from concurrent SGA and ART is indicated in all patients receiving these medication combinations.
doi:10.1016/j.psychres.2014.04.015
PMCID: PMC4082695  PMID: 24794030
HIV; cardiovascular risk; serious mental illness; diabetes mellitus; obesity; hypertriglyceridemia; hypertension
17.  Correlation of major depressive disorder symptoms with FKBP5 but not FKBP4 expression in human immunodeficiency virus–infected individuals 
Journal of Neurovirology  2010;16(5):399-404.
Major depressive disorder (MDD) is a significant cause of morbidity in people living with the human immunodeficiency virus (HIV). FKBP5 is a candidate gene with single-nucleotide polymorphisms (SNPs) rs1360780 and rs3800373 associated with MDD. This gene product and its relative, FKBP4, physically associate with the glucocorticoid receptor whose function is implicated in MDD pathophysiology. Because these genes are expressed in blood and brain and elevated in HIV infection, we explored the relationship between gene expression, genotype, and MDD symptoms. Longitudinally followed subjects (N = 57) as part of the CNS HIV AntiRetroviral Effects Research study, with diagnosed MDD and who donated blood for genotyping and gene expression analysis, were assessed. Subjects donated blood on adjacent visits with and without meeting criteria for MDD episode. Changes in clinical parameters were compared changes in gene expression. Change in FKBP5 expression correlated with change in Beck Depression Inventory (BDI) for MDD → euthymic comparison in GG genotype of rs3800373 (P = .013) and TT carriers of rs1360780 (P = .02). In euthymic → MDD comparison, GG homozygous, FKBP5 expression correlated with more severe change in BDI. Change in FKBP4 expression did not correlate with changes in clinical or depression measurements. Higher FKBP5 expression correlated with greater symptom change for GG carriers of rs3800373.
doi:10.3109/13550284.2010.504248
PMCID: PMC3274491  PMID: 20726698
FKBP4; FKBP5; gene expression; genotyping; HIV; human immunodeficiency virus; major depression; major depressive disorder
18.  Efavirenz concentrations in CSF exceed IC50 for wild-type HIV 
Objectives
HIV-associated neurocognitive disorders remain common despite use of potent antiretroviral therapy (ART). Ongoing viral replication due to poor distribution of antivirals into the CNS may increase risk for HIV-associated neurocognitive disorders. This study's objective was to determine penetration of a commonly prescribed antiretroviral drug, efavirenz, into CSF.
Methods
CHARTER is an ongoing, North American, multicentre, observational study to determine the effects of ART on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within 1 h of each other from subjects taking efavirenz between September 2003 and July 2007. Samples were assayed by HPLC or HPLC/mass spectrometry with detection limits of 39 ng/mL (plasma) and <0.1 ng/mL (CSF).
Results
Eighty participants (age 44 ± 8 years; 79 ± 15 kg; 20 females) had samples drawn 12.5 ± 5.4 h post-dose. The median efavirenz concentrations after a median of 7 months [interquartile range (IQR) 2–17] of therapy were 2145 ng/mL in plasma (IQR 1384–4423) and 13.9 ng/mL in CSF (IQR 4.1–21.2). The CSF/plasma concentration ratio from paired samples drawn within 1 h of each other was 0.005 (IQR 0.0026–0.0076; n = 69). The CSF/IC50 ratio was 26 (IQR 8–41) using the published IC50 for wild-type HIV (0.51 ng/mL). Two CSF samples had concentrations below the efavirenz IC50 for wild-type HIV.
Conclusions
Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wild-type IC50 in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.
doi:10.1093/jac/dkq434
PMCID: PMC3019085  PMID: 21098541
CNS; pharmacology; non-nucleoside reverse transcriptase inhibitors
19.  HIV-Associated Distal Neuropathic Pain is Associated with Smaller Total Cerebral Cortical Gray Matter 
Journal of neurovirology  2014;20(3):209-218.
Despite modern antiretroviral therapy, HIV-associated sensory neuropathy affects over 50% of HIV patients. The clinical expression of HIV neuropathy is highly variable: many individuals report few symptoms, but about half report distal neuropathic pain (DNP), making it one of the most prevalent, disabling and treatment-resistant complications of HIV disease. The presence and intensity of pain is not fully explained by the degree of peripheral nerve damage, making it unclear why some patients do, and others do not, report pain. To better understand central nervous system contributions to HIV DNP, we performed a cross-sectional analysis of structural magnetic resonance imaging (MRI) volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Antiretroviral Treatment Effects Research Study, CHARTER). The association between DNP and the structural imaging outcomes was investigated using both linear and nonlinear (Gaussian Kernel support vector) multivariable regression, controlling for key demographic and clinical variables. Severity of DNP symptoms was correlated with smaller total cerebral cortical gray matter volume (R = −0.24; p = 0.004). Understanding the mechanisms for this association between smaller total cortical volumes and DNP may provide insight into HIV DNP chronicity and treatment-resistance.
doi:10.1007/s13365-014-0236-8
PMCID: PMC4040150  PMID: 24549970
HIV Distal Neuropathic Pain; Structural MRI; Cortical Volume
20.  Corrigendum 
Journal of neurovirology  2010;16(2):185-188.
doi:10.3109/13550284.2010.481820
PMCID: PMC4386597  PMID: 20443740
21.  Dynamic Indices of Methamphetamine Dependence and HIV Infection Predict Fluctuations in Affective Distress: A Five-year Longitudinal Analysis 
Journal of affective disorders  2013;151(2):10.1016/j.jad.2013.07.036.
Background
Methamphetamine (METH) use and human immunodeficiency virus (HIV) infection are highly comorbid, and both are associated with increased prevalence of affective distress. Delineating the trajectory of affective distress in the context of METH dependence and HIV infection is important given the implications for everyday functional impairment, adverse health behaviors, and increased risk for adverse health outcomes.
Methods
We conducted a five-year longitudinal investigation involving 133 METH-dependent (74 HIV seropositive) and 163 non-METH-dependent (90 HIV seropositive) persons to examine both long-standing patterns and transient changes in affective distress. Mixed-effect regression models with random subject-specific slopes and intercepts evaluated the effect of METH dependence, HIV serostatus, and related variables on affective distress, as measured by the Profile of Mood States.
Results
Transient changes in affective distress were found to be greater among those with a diagnosis of current MDD, briefer durations of abstinence from METH, and higher quantity of METH consumed. Weak associations were observed among static (time-independent predictors) covariates and long-standing patterns in affective distress.
Limitations
Study lacked data pertaining to the participants’ involvement in METH treatment and relied on respondent-driven sampling.
Conclusions
Our longitudinal investigation of the trajectory of affective distress indicated that specific and dynamic indices of current METH use were associated with greater transient changes in mood. In the evaluation and treatment of affective distress, recency and quantity of current METH use are important to consider given their association with heightened affective distress and mood instability over time.
doi:10.1016/j.jad.2013.07.036
PMCID: PMC3845675  PMID: 24012068
Affective distress; Methamphetamine; Dependence; HIV; Longitudinal
22.  Neuropsychiatric Aspects of HIV Infection 
Western Journal of Medicine  1989;151(3):313-314.
PMCID: PMC1026869  PMID: 18750639
23.  Etravirine in CSF is highly protein bound 
Objectives
Etravirine has high affinity for plasma drug-binding proteins, such as albumin and α1-acid glycoprotein, which limits the amount of unbound etravirine available to enter the CNS. The objective of this study was to compare total and unbound etravirine concentrations in CSF with plasma concentrations and the in vitro median inhibitory concentration (IC50) for wild-type HIV (0.9 ng/mL).
Methods
Total and bound etravirine concentrations were measured in 17 CSF and plasma pairs by isotope-dilution liquid chromatography tandem mass spectroscopy, radioligand displacement and ultracentrifugation. Unbound etravirine concentrations were calculated from the bound fraction. The dynamic range of the assay was 7.8–2000 (plasma) and 0.78–200 (CSF) ng/mL.
Results
Subjects were mostly middle-aged (median 43 years) white (78%) men (89%). All CSF etravirine concentrations were above the limit of quantification. Total and unbound median etravirine concentrations in CSF were 9.5 (IQR 6.4, 26.4) and 0.13 (IQR 0.08, 0.27) ng/mL, respectively. Etravirine was 96% (IQR 94.5, 97.2) protein bound in plasma and 98.4% (IQR 97.8, 98.8) in CSF. Total etravirine in CSF was 4.3% (IQR 3, 5.9) of total and 101% (IQR 76, 160) of unbound etravirine in plasma. There were no significant correlations between unbound etravirine concentrations and concentrations of albumin in plasma or CSF. Unbound etravirine concentrations in CSF did not reach the wild-type IC50 in any of the specimens.
Conclusions
Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS.
doi:10.1093/jac/dks517
PMCID: PMC3625433  PMID: 23335197
HIV; antiretroviral therapy; central nervous system; CNS; protein binding; CSF
24.  Risks and predictors of current suicidality in HIV-infected heroin users in treatment in Yunnan, China: A controlled study 
Objective
Suicide is an important public health problem in China. Elsewhere injection drug use and HIV infection have independently been associated with suicidality, but research has often overlooked these high-risk groups in China. We determined the frequency and predictors of suicidal ideas in Chinese, HIV-infected (HIV+) and uninfected (HIV-) heroin injection drug users in treatment (IDUs) and a control sample. We hypothesized that rates of suicidal ideas would be significantly higher among IDUs compared to controls, and highest among HIV+ IDUs.
Method
We assessed suicidal ideas within the past two weeks in HIV+ (N = 204) and HIV- (N = 202) heroin IDUs in methadone treatment in Yunnan, a province at the intersection of the heroin and HIV epidemics, and in demographically matched, uninfected non-drug using controls (N = 201).
Results
Rates of suicidality were higher in IDUs than controls but there was no additive effect of HIV infection (HIV+ IDU 43.1%; HIV- IDU 37.1%; controls 8.5%). Among HIV+ IDUs suicidality was associated most strongly with a combination of prior history of major depression, low perceived social support, and experience of HIV-relevant stress, but not with AIDS diagnosis. Among HIV- IDUs suicidality was associated with prior history of major depressive or alcohol use disorder. Less than 25% of IDUs with suicidality had histories of mood or alcohol use diagnoses.
Conclusion
Because suicidal ideation is frequent in IDUs in China, regardless of HIV status, and is not fully accounted for by past psychiatric history, additional research may be warranted.
doi:10.1097/QAI.0b013e31827ce513
PMCID: PMC3975910  PMID: 23196829
IV drug use; HIV; Depression; Suicide; China
25.  Relationships Among Neurocognitive Status, Medication Adherence Measured by Pharmacy Refill Records, and Virologic Suppression in HIV-infected Persons 
Background
Optimal antiretroviral therapy (ART) effectiveness depends upon medication adherence, which is a complex behavior with many contributing factors including neurocognitive function. Pharmacy refill records offer a promising and practical tool to assess adherence.
Methods
A substudy of the CHARTER (CNS HIV Anti-Retroviral Therapy Effects Research) study was conducted at the Johns Hopkins University (JHU) and the University of Washington (UW). Pharmacy refill records were the primary method to measure ART adherence, indexed to a “sentinel” drug with the highest central nervous system penetration effectiveness score.
Standardized neuromedical, neuropsychological, psychiatric and substance use assessments were performed at enrollment and at 6 months. Regression models were used to determine factors associated with adherence and the relationships between adherence and change in plasma and cerebrospinal fluid HIV RNA concentrations between visits.
Results
Among 80 (33 JHU, 47 UW) participants, the mean adherence score was 86.4% with no difference by site. In the final multivariable model, better neurocognitive function was associated with better adherence, especially among participants who were at JHU, male, and HIV-infected for a longer time-period. Worse performance on working memory tests was associated with worse adherence. Better adherence predicted greater decreases in cerebrospinal fluid HIV RNA between visits.
Conclusion
Poorer global neurocognitive functioning and deficits in working memory were associated with lower adherence defined by a pharmacy refill record measure, suggesting that assessments of cognitive function, and working memory in particular, may identify patients at risk for poor ART adherence who would benefit from adherence support.
doi:10.1097/QAI.0b013e31827ed678
PMCID: PMC3906725  PMID: 23202813
HIV; adherence; cognitive impairment; pharmacy refill records; HAND; CPE

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